Raloxifene sprinkle composition

ABSTRACT

The present invention relates to a capsule composition of raloxifene comprising multiparticulates, comprising a) a core comprising raloxifene; and b) a taste-masking coating present in an amount of from about 15% to about 80% w/w based on the total weight of the composition.

RELATED APPLICATIONS

This is a continuation application of U.S. application Ser. No.15/608,387, filed May 30, 2017 which claims priority to IndianApplication IN201611018447, filed May 30, 2016, each of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a capsule composition comprisingplurality of particulates comprising a) a core comprising raloxifene,and b) a taste-masking coating present in an amount of from about 0.5%to about 50% w/w based on the core weight.

BACKGROUND OF THE INVENTION

Raloxifene is indicated for the treatment of osteoporosis and breastcancer in postmenopausal women. It is commercially available asimmediate release tablets (Evista®) in the U.S. The development ofraloxifene composition has been hindered, due to low water solubilitywhich can adversely affect the bioavailability and manufacturingprocess. U.S. Pat. No. 6,458,811 discloses raloxifene having a meanparticle size of less than 25 microns, which allows enhancedbioavailability and control during the manufacturing process. It furtherdiscloses granular compositions comprising raloxifene, which can becompressed into tablet dosage forms or can be filled into capsules.

Raloxifene is known to possess a bitter taste. Raloxifene is categorizedas a drug that should be “handled as hazardous” by the NationalInstitute for Occupational Safety and Health (U.S.). Further, thesummary of product characteristic by the European Medicines Agencyinstructs to “not break or crush” Evista® tablets, as they may tastebad. Handling of uncoated granules and crushed tablets would also behazardous for the compounding pharmacist.

Thus, there exists a need in the art to formulate a composition ofraloxifene which provides for better patient compliance for patientsthat have difficulty in swallowing. However, masking the bitter taste aswell as achieving the desired immediate release profile would bechallenging for a drug with poor aqueous solubility.

Hence, the present inventors have now developed plurality ofparticulates of raloxifene, which can be administered by sprinklingmultiparticulates on soft food and have a desired in-vitro release. Thepresent invention would provide advantages for patients who havedifficulty in swallowing the conventional solid oral composition.Further, the sprinkle composition of the present invention has highdrug-loading, leading to a minimal total weight of the composition,which can be easily handled and taken by the patients.

SUMMARY OF THE INVENTION

The present invention relates to a capsule composition comprisingplurality of particulates comprising a) a core comprising raloxifene,and b) a taste-masking coating present in amount of from about 0.5% toabout 50% w/w based on the core weight.

The present invention can be administered as an intact capsule as wellas a sprinkle composition.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to a capsule compositionof raloxifene comprising plurality of particulates s, wherein saidcapsules release not more than 40% of raloxifene in 10 minutes, whenmeasured in a United States Pharmacopeia (USP) type 2 dissolutionapparatus, paddle at 50 RPM, at a temperature of 37° C.±0.5° C. in 1000mL of pH 4.5 acetate buffer and 0.05% sodium lauryl sulfate.

A second aspect of the present invention relates to a capsulecomposition of raloxifene comprising plurality of particulates, whereinsaid capsules release not more than 85% of raloxifene in 10 minutes,when measured in a USP type 2 dissolution apparatus, paddle at 100 RPM,at a temperature of 37° C.±0.5° C. in 1000 mL of water, 0.5%polysorbate, and an enzyme.

According to one embodiment of this aspect, the raloxifene may bepresent in an amount of from about 10% to about 80% based on the totalweight of composition. In particular, from about 15% to about 80% basedon the total weight of composition, wherein the capsule shell weight isnot included in the total weight of composition.

A third aspect of the present invention relates to a capsule compositionof raloxifene comprising multiparticulates having raloxifene in anamount of from about 10% to about 80%, e.g. about 20% to about 60%, orabout 30 to about 40%, based on the total fill weight of the capsule,where said capsule is bioequivalent to the marketed raloxifene tablets.

According to one embodiment of this aspect, the total fill weight isless than about 600 mg. In particular, the total fill weight is betweenabout 75 mg and about 600 mg, wherein the capsule shell weight is notincluded into the total fill weight of the capsule.

According to another embodiment of this aspect, the capsule size is 0 orless. In particular, the capsule size is 1 or less.

Bioequivalence is established by comparing pharmacokinetic parameters,for example AUC and C_(max), of the intact capsule composition of thepresent invention with Evista® tablets in healthy human subjects.

The term “AUC” refers to the area under the time/plasma concentrationcurve following administration of a raloxifene pharmaceuticalcomposition.

The term “C_(max)” refers to the maximum concentration of raloxifene inthe blood following the administration of a raloxifene pharmaceuticalcomposition.

According to another embodiment of this aspect, the capsules, whenadministered to healthy subjects under fasting conditions, provide amean C_(max) value in the range of from about 2.5 ng/mL/mg to about 15ng/mL/mg.

According to one embodiment of the above aspects, the multiparticulateshave a bulk density of from about 0.30 g/mL to about 0.80 g/mL.

According to another embodiment of the above aspects, themultiparticulates may be in the form of a core and coating.

According to another embodiment of the above aspects, the coating ispresent in an amount of from about 0.5% to about 40% w/w based on thecore weight.

According to another embodiment of the above aspects, the raloxifene hasa D₉₀ particle size of not more than 35 μm.

According to another embodiment of the above aspects, the coated coreshave a D₉₀ particle size of less than or equal to 900 μm, e.g., equal toabout 800 μm, for example, about 200 to about 500 microns, e.g., about800 μm, or e.g., having about 60 to about 40 ASTM sieve size.

The term “D₉₀ value” as used in this application, means that 90% of theextended release coated cores have a volume diameter in the specifiedrange when measured by a light scattering method such as a Malvern®Mastersizer®.

According to another embodiment of the above aspects, the coating is ataste-masking coating.

According to another embodiment of the above aspects, the taste-maskingcoating comprises a taste-masking polymer.

According to another embodiment of the above aspects, the taste-maskingcoating further comprises a sweetener.

According to another embodiment of the above aspects, the particulatesare further blended with a lubricant.

According to another embodiment of the above aspects, the lubricant ispresent in an amount of from about 0.1% to about 15% by total weight ofthe composition.

According to another embodiment of the above aspects, the particulatesare further blended with disintegrants.

According to another embodiment of the above aspects, the capsulecomposition is stable when subjected to stability conditions at atemperature of 40° C. and relative humidity (“RH”) of 75% for a period 6months.

According to another embodiment of the above aspects, the stablesprinkle capsule composition, when sprinkled on soft food, is notimpacted by soft foods of different pH levels.

According to another embodiment of the above aspects, the stablesprinkle capsule composition, produce relative substance not more than1% w/w when sprinkled on soft food for at least 30 minutes.

The term “stable” as used herein means that the capsule composition,when subjected to stability conditions at a temperature of 40° C. and RHof 75% for a period 6 months, produces the raloxifene-related compound Cnot more than 1%. Further, the particulates are stable for at least 60minutes after being sprinkled onto soft foods of different pH levels.

According to another embodiment of the above aspects, the raloxifene isnot present in intimate contact with an alkaline excipient.

“Intimate contact” as used herein means that alkaline excipients arepresent in the core or the coating dispersion together with raloxifene.

Alkaline excipients used herein may include but are not limited tocalcium phosphate, magnesium phosphate, aluminum phosphate, magnesiumcarbonate, croscarmellose, and mixtures thereof.

The term “raloxifene” refers to raloxifene base, as well as otherpharmaceutically acceptable salts, in particular hydrochloride.Raloxifene may be present in the sprinkle composition in an amount offrom about 20 mg to about 100 mg. Raloxifene may be present in an amountof from about 15% to about 80% based on the total weight of composition.

The term “sprinkle composition” as used herein refers to a compositionwhich can be sprinkled onto soft foods such as apple sauce, yogurt,cottage cheese, and pudding, or into drinks, and then administeredorally to patients. The composition may also be administered through anNG-tube or a G-tube in patients who cannot swallow.

The term particulates” as used herein includes pellets, beads, granules,spheres, and mini-tablets. These particulates may be in the form ofcoated cores. The coated cores may have single or multiple coatings. Thecoated cores may be prepared by coating raloxifene, optionally alongwith other pharmaceutically acceptable excipients, onto an inert bead.Optionally, a seal coat layer may be present between the inert beads andsaid coating layer comprising raloxifene. The coated cores may befurther coated, preferably by a taste-masking coating. The inert beadsmay be water-soluble, water-swellable, or water-insoluble. Examples ofwater-swellable cores include microcrystalline cellulose spheres such asCelphere®. Examples of water-soluble cores include sugar spheres made ofglucose, mannitol, lactose, xylitol, dextrose, sucrose, and combinationsthereof. Examples of water-insoluble cores include glass beads andsilicon dioxide beads. The inert cores have a D₉₀ particle size of lessthan or equal to about 800 μm.

According to another embodiment of the above aspects, the coated coresare prepared by coating with a raloxifene dispersion in an amount offrom about 80% to about 150% by total weight of the inert cores.

According to another embodiment of the above aspects, the raloxifenedispersion comprises a surfactant.

Alternatively, the particulates may be in the form of matrix cores,formulated by mixing raloxifene, optionally with other pharmaceuticallyacceptable excipients, followed by granulation, direct compression, orextrusion-spheronization. Optionally, the matrix cores may be coated.

A fourth aspect of the present invention relates to a capsulecomposition comprising a plurality of particulates comprising

-   -   a) a core comprising raloxifene; and    -   b) a taste-masking coating over the core        wherein the taste-masking coating is present in an amount of        from about 0.5% to about 50%, or about 0.5% to about 40% w/w,        e.g., about 10% to about 30% or 40% w/w based on the core        weight.

The taste masking coating may comprise one or more taste-maskingpolymers and coating additives. Pharmaceutically acceptable coatingadditives may be sweeteners, pore-formers, plasticizers, anti-tackingagents, opacifiers, coloring agents, disintegrants, coating agents, andmixtures thereof.

Suitable taste-masking polymers are selected from the group comprisingwater soluble/water swellable polymers such as hydroxy ethyl cellulose,hydroxy propyl cellulose, and hypromellose; water insoluble polymerssuch as ethyl cellulose, polycarbophil, and polyacrylic acid; andmixtures thereof. Taste-masking polymers may also be enteric, such ascellulose acetate butyrate, cellulose acetate phthalate, ethyl vinylphthalate, polyvinyl acetate phthalate, hydroxy alkyl cellulosephthalates, methacrylic acid/ethyl acrylate copolymers, and mixturesthereof. In particular, the taste-masking polymer is a water-insolublepolymer, for example ethyl cellulose. In particular, the taste-maskingpolymer is a water-soluble polymer, alone or in combination with awater-insoluble polymer. These may be present in the composition in therange of from about 0.01% w/w to about 25% w/w of the composition.

Examples of pore-formers include calcium carbonate, calcium phosphate,calcium saccharide, calcium succinate, calcium tartrate, ferric acetate,ferric hydroxide, ferric phosphate, magnesium carbonate, magnesiumcitrate, magnesium hydroxide, magnesium phosphate, hypromellose such asHPMC E5, and mixtures thereof. These may be present in the compositionin the range of from about 0.01% w/w to about 15% w/w of thecomposition.

Examples of sweeteners include, but are not limited to, sucrose,sucralose, sorbitol, xylitol, dextrose, fructose, maltitol, acesulfamepotassium, aspartame, saccharin, saccharin sodium, maltitol, glucose,cyclamate, sodium cyclamate, and mixtures thereof. These may be presentin the composition in the range of from about 0.1% w/w to about 20% w/wof the total weight of the composition.

Examples of plasticizers include propylene glycol, triethyl citrate,tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glycerylmonostearate, triacetin, polyethylene glycol, diethyl phthalate,acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol,and mixtures thereof.

Examples of anti-tacking agent include talc, glyceryl monostearate,vegetable oil, waxes, a blend of magnesium stearate and sodium laurylsulfate, boric acid, sodium benzoate, sodium acetate, sodium chloride,polyethylene glycol, sodium oleate, sodium lauryl sulfate, magnesiumlauryl sulfate, corn starch, amorphous silicon dioxide, Vitamin E,Vitamin E TPGS, and mixtures thereof.

Examples of opacifiers include titanium dioxide, manganese dioxide, ironoxide, silicon dioxide, and mixtures thereof. These may be present inthe composition in the range of from about 0.01% w/w to about 15% w/w ofthe composition, e.g., about 1% w/w to about 4% w/w.

Suitable solvents are selected from the group comprising purified water,ethyl alcohol, isopropyl alcohol, acetone, and mixtures thereof.

Coating may be carried out by using any conventional coating techniquesknown in the art, such as spray coating using a fluidized bed processoror pan coating.

The pharmaceutical composition may further comprise otherpharmaceutically acceptable excipients. Examples of pharmaceuticallyacceptable excipients include binders, diluents, lubricants/glidants,disintegrants, surfactants, and mixtures thereof.

Examples of fillers or diluents include, but are not limited to,lactose, sorbitol, calcium dihydrogen phosphate dihydrate, calciumphosphate-dibasic, calcium phosphate-tribasic, calcium sulfate,microcrystalline cellulose, silicified microcrystalline cellulose,mannitol, starch, pregelatinized starch, and mixtures thereof.

Examples of binders include, but are not limited to, corn starch,pregelatinized starch, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, methyl cellulose, hydroxypropyl cellulose(HPC-L), methylcellulose, carboxymethyl cellulose sodium, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and mixtures thereof.

Examples of disintegrants include, but are not limited to, cross-linkedpolyvinyl pyrrolidone, corn starch, modified starches, agar-agar,calcium carbonate, sodium carbonate, alginic acids, croscarmellosesodium, sodium starch glycolate, microcrystalline cellulose,hydroxypropyl cellulose (L-HPC), and mixtures thereof. These may bepresent intragranularly or extragranularly. The disintegrant may beadded at the lubrication stage.

Examples of lubricants and glidants include, but are not limited to,colloidal anhydrous silica, croscarmellose sodium, stearic acid,magnesium stearate, glyceryl behenate, calcium stearate, sodium stearylfumarate, talc, microcrystalline wax, yellow beeswax, white beeswax, andmixtures thereof.

Examples of surfactants include, but are not limited to, sorbitanmonostearate, polyoxyethylene sorbitan monostearate such as polysorbate60 or polysorbate 80, non-ethoxylated glyceryl monostearate,cetomacrogol, cetostearyl alcohol, sodium stearoyl lactylate, lecithin,sodium lauryl sulfate and mixtures thereof.

The coloring agents and flavoring agents of the present invention may beselected from any FDA-approved colors or flavors for oral use.

The disclosure also provides for a plurality of particulates, forexample, contained within a capsule, wherein each particulate comprisesan inert core; a drug layer disposed on the inert core, where the druglayer comprises raloxifene hydrochloride and a polymer such as povidone;a taste masking layer over the drug layer, comprising a polymer such ashypromellose and optionally a sweetener (e.g., sucralose), andoptionally a lubricant layer over the taste masking layer, comprisinge.g., at least one of sodium stearyl fumarate, silicon dioxide, andcroscarmellose sodium (e.g., equal parts by weight).

The term “about,” as used herein, refers to any value which lies withinthe range defined by a variation of up to ±10% of the value.

The following examples represent various embodiments according to thepresent invention. The examples are given solely for the purpose ofillustration and are not to be construed as limitations of the presentinvention, as many variations thereof are possible without departingfrom the spirit and scope of the invention.

Example 1

Ingredients Quantity (mg) Drug layered cores Raloxifene hydrochloride60.00 Sugar spheres 60.00 Polysorbate 80 4.00 Povidone 9.00 Sucralose2.00 Purified water q.s. Taste-masking coating Ethyl cellulose 3.88Hypromellose 15.47 Talc 4.17 Magnesium stearate 2.00 Sucralose 0.50Isopropyl alcohol q.s. Purified water q.s. Lubrication Sodium stearylfumarate 1.62 Colloidal silicon dioxide 1.62 Croscarmellose sodium 1.62Manufacturing Process:

-   1. Raloxifene, povidone, polysorbate 80, and sucralose were    dispersed in purified water to obtain a drug dispersion.-   2. Sugar spheres were coated with the drug dispersion of step 1 to    obtain drug layered cores.-   3. Hypromellose, ethyl cellulose, magnesium stearate, sucralose, and    talc were dispersed in a mixture of isopropyl alcohol and purified    water to obtain a dispersion.-   4. The drug coated cores of step 2 were coated with the dispersion    of step 3 to obtain taste-masked coated cores.-   5. Sodium stearyl fumarate, croscarmellose sodium, and colloidal    silicon dioxide were mixed with the taste-masked coated cores of    step 4 to obtain lubricated coated cores.

Example 2

The lubricated coated cores of Example 1 were filled into size 2capsules.

Example 3

Quantity Ingredients (mg/capsule) Drug layered cores Raloxifenehydrochloride 60.00 Sugar spheres 60.00 Polysorbate 80 4.00 Povidone9.00 Sucralose 2.00 Purified water q.s. Taste-masking coatingHypromellose 13.50 Sucralose 6.00 Talc 5.50 Magnesium stearate 2.00Purified water q.s. Lubrication Sodium stearyl fumarate 1.62 Colloidalsilicon dioxide 1.62 Croscarmellose sodium 1.62Manufacturing Process:

-   1. Raloxifene, povidone, polysorbate 80, and sucralose were    dispersed in purified water to obtain a drug dispersion.-   2. Sugar spheres were coated with the drug dispersion of step 1 to    obtain drug layered cores.-   3. Hypromellose, magnesium stearate, sucralose, and talc were    dispersed in purified water to obtain a dispersion.-   4. The drug coated cores of step 2 were coated with the dispersion    of step 3 to obtain taste-masked coated cores.-   5. Sodium stearyl fumarate, croscarmellose sodium, and colloidal    silicon dioxide were mixed with the taste-masked coated cores of    step 4.-   6. The lubricated coated cores of step 5 were filled into suitable    sized capsules, e.g., capsule size 2.

Example 4

Ingredient mg/capsule Drug layered cores Raloxifene hydrochloride USP60.000 Sugar spheres (40/60 mesh ASTM) 60.000 Polysorbate 80 4.000Povidone 9.000 Sucralose 2.000 Purified water q.s. Taste-masking coatingEthyl cellulose 3.867 Hypromellose 15.465 Talc 4.168 Magnesium stearate2.000 Sucralose 1.500 Isopropyl alcohol q.s. Purified water q.s.Lubrication Sodium stearyl fumarate 1.620 Colloidal silicon dioxide1.620 Croscarmellose sodium 1.620Manufacturing Process:

-   1. Raloxifene, povidone, polysorbate 80, and sucralose were    dispersed in purified water to obtain a drug dispersion.-   2. Sugar spheres were coated with the drug dispersion of step 1 to    obtain drug layered cores.-   3. Hypromellose, ethyl cellulose, magnesium stearate, sucralose, and    talc were dispersed in a mixture of isopropyl alcohol and purified    water to obtain a dispersion.-   4. The drug coated cores of step 2 were coated with the dispersion    of step 3 to obtain taste-masked coated cores.-   5. Sodium stearyl fumarate, croscarmellose sodium, and colloidal    silicon dioxide were mixed with the taste-masked coated cores of    step 4 to obtain lubricated coated cores.-   6. The lubricated coated cores of step 5 were filled into size 2    capsules.    Dissolution Study of Example 1 in Dissolution Media I

The dissolution study was performed in 1000 mL of pH 4.5 acetate bufferand 0.05% sodium lauryl sulfate in USP II apparatus at 50 RPM. Thesamples were analyzed by high performance liquid chromatography(HPLC)/UV.

Dissolution Study of Example 4 in Dissolution Media II

The dissolution study was performed in 1000 mL of water, 0.5%polysorbate, and pepsin (pepsin may be replaced with bromelain) in USPII apparatus at 100 RPM. The samples were analyzed by HPLC/UV.

TABLE 1 Percentage release of Example 1 and Example 4 in dissolutionmedia I and II Time (minutes) Percent drug release 10 20 30 45 Example 123 29 33 37 Dissolution media I Example 4 75 88 94 97 Dissolution mediaII

Table 1 shows that Examples 1 and 4 produced desired in-vitro profilesin dissolution media I and dissolution media II.

Pharmacokinetic Parameters of Example 4 Capsules and Evista® Tablets inHealthy Human Subjects

Pharmacokinetic studies were conducted by orally administering Example 4capsules and Evista® tablets to healthy human subjects under fastingconditions.

A single dose randomized, three treatment, four period, four sequencecrossover study in healthy human subjects was carried out under fastingconditions to determine pharmacokinetic parameters.

TABLE 2 Pharmacokinetic parameters for Example 4 capsules and Evista ®tablets Pharmacokinetic parameters Ratio (T/R) C_(max) (ng/mL) 111.13AUC_(0-inf) (ng · hr/mL) 112.66

TABLE 3 Pharmacokinetic parameters Example 4 Mean C_(max) (ng/mL/mg) 7.0

Table 2 shows that Example 4 capsules were found to be bioequivalent tothe marketed raloxifene tablets.

Stability:

In Vitro Soft Food Studies

a) Related Substances

A capsule of Example 4 was opened, and the particulates therein weretested for related substances after exposure to applesauce or chocolatepudding for 60 minutes.

The coated discrete units were found to be stable in applesauce andchocolate pudding, with regard to related substances as given in Table4.

TABLE 4 Related substances of particulates after exposure to applesauceand chocolate pudding Exposure Exposure time Exposure Exposure time 0min 60 min time 0 min time 60 min (chocolate (chocolate (applesauce)(applesauce) pudding) pudding) Impurity-C (Related 0.06 0.06 0.02 0.03Compound C) (% w/w) Total related 0.15 0.17 0.13 0.13 substances (% w/w)b) Assay

A capsule of Example 4 was opened, and the multiparticulates thereinwere tested for assay after exposure to various soft foods for 60minutes. The multiparticulates were found to be stable with regard toassay, as given in Table 5.

TABLE 5 Assay of coated discrete units after exposure to various softfoods Soft food Exposure time 0 min Exposure time 60 min Applesauce101.7% 101.6% Yogurt 100.5% 99.2% Pudding 98.3% 97.8%

Based on the in vitro soft food studies, it was concluded that stabilityis not impacted by soft foods having different pH levels.

We claim:
 1. A capsule composition comprising a plurality ofparticulates, wherein each particulate comprises: a) a core comprisingraloxifene; and b) a taste-masking coating over the core to form coatedcores having a D₉₀ particle size of less than or equal to 900 μm;wherein raloxifene is present in an amount of from about 15% to about80% based on the total weight of the composition.
 2. The capsulecomposition according to claim 1, wherein the total fill weight of thecapsule is from about 75 mg to about 600 mg.
 3. The capsule compositionaccording to claim 1, wherein the particulates further include alubricant, which is present in an amount of from about 0.1% to about 15%by total weight of the composition.
 4. The capsule composition accordingto claim 1, wherein the taste-masking coating comprises a taste-maskingpolymer selected from the group consisting of water-soluble polymers,water-swellable polymers, water-insoluble polymers, enteric polymers. 5.The capsule composition according to claim 4, wherein the taste-maskingcoating further comprises a sweetener.
 6. The capsule compositionaccording to claim 1, wherein the capsule composition is stable whensubjected to stability conditions at a temperature of 40° C. andrelative humidity (“RH”) of 75% for a period 6 months.
 7. A capsulecomposition comprising a plurality of particulates, wherein eachparticulate comprises: a) a core comprising raloxifene; and b) ataste-masking coating over the core; wherein raloxifene is present in anamount of from about 15% to about 80% based on the total weight of thecomposition.